Focal and segmental glomerulosclerosis (FSGS) is a significant cause of end-stage renal disease. It is particularly prevalent in black patients and data suggests its prevalence is increasing. Despite compelling evidence for genetic components in sporadic FSGS, it is very difficult to find causative genes in this group due to the diverse etiology of the syndrome. Therefore, we have taken a complimentary approach of collecting families with rare, Mendelian disease, to find genes that may be relevant to the more common sporadic disease. The study of these individual genes also provides an opportunity to understand the pathophysiology of this syndrome. We have previously described linkage to chromosome 11q in a large autosomal dominant FSGS family from New Zealand (FSGS2) and recently discovered the genetic mutatior in these kindred. In an effort to further characterize and elucidate the spectrum of disease-causing mutations in familial FSGS, we propose to (1) Identify novel genes that cause FSGS by (la) establishing linkage in FSGS families already screened for 457 markers. Several regions of interest for follow-up have been identified and will be examined by typing additional markers and (lb) we will define the MCI for any newly identified loci from specific aim 1 by fine-mapping the region and via haplotype analysis to identify critical recombinations. After the MCI is defined candidate gene analysis will commence. (2) Maximize phenotypic data and power of selected FSGS families to aid linkage studies by completing ascertainment and expansion. We will begin our ascertainment efforts immediately by expanding the three families from the genomic screen (families 6543, 6510 and 6524). Based on family history data, we anticipate that additional affected individuals will be identified from the natural progression of kidney disease in individuals from the unknown category since original ascertainment. We will focus next on expanding families from our FSGS dataset that have the greatest linkage potential. Lastly, (3) Determine the prevalence of mutations in genes that are known to cause inherited glomerular diseases in the Duke FSGS dataset. We will sequence our recently identified gene, NPHS1, NPHS2 and ACTN4 genes in all probands in our large cohort of families with FSGS. These studies will further define the genetic pathogenesis of inherited FSGS. New mutations found in the genes known to cause FSGS will enhance our understanding of the genetics and biology of thi., disorder, takin 9 advantage of our entire resource of families.